The present proposed research is designed to utilize the pentobarbital pellet implantation technique developed in this laboratory for further quantification of the physical dependence on pentobarbital after withdrawal. Studies will be further undertaken on the contributory role of the putative neurotransmitters involved in acute pentobarbital effects and in the development of tolerance to and physical dependence on barbiturates. Studies will also be carried out on the application of this model for investigating the interactions of continuous administration of barbiturates with other drugs of abuse. The research plan proposes (1) systematic quantification of physical dependence on pentobarbital after withdrawal; (2) assessment of the contributory role of putative neurotransmitters in the central nervous system involved in acute pentobarbital effect and during the development of tolerance and physical dependence; (3) assessment of the effects of pharmacological manipulation on the development of pentobarbital tolerance and physical dependences; (4) assessment of hepatic drug metabolizing enzyme inhibitors on pentobarbital tolerance and physical dependence; (5) application of this model for studying the interactions of continuous administration of barbiturates and other drugs of abuse such as non-barbiturate type sedative-hypnotics, e.g., benzodiazepines, methaqualone, ketamine, and alcohols; (6) application of a similar technique to study the long acting barbiturate, barbital, to examine if there is a common mechanism in terms of CNS tolerance to and physical dependence on barbiturates; and (7) to study any affirmative findings in higher mammalian species. Hopefully, it will be possible to develop pharmacological agents for clinical application which would prevent the development of barbiturate tolerance and physical dependence without modifying therapeutic and hypnotic efficacies.